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Background Focal therapy (FT) for prostate cancer is less invasive than radical treatment but carries a risk of recurrence. Salvage robot-assisted radical prostatectomy (S-RARP) is a possible option after FT failure. Objective To evaluate the impact of FT on functional and oncological outcomes following S-RARP. Design, setting, and participants In a retrospective analysis of data from a prospectively collected institutional database, 53 patients who underwent S-RARP following failure of focal ablation were selected as group I; patients who had whole-gland ablation and external beam therapy were excluded. This group was matched to a control sample (matched at ratios of 1:1, 1:2, 1:3, 1:4) of men who had undergone primary RARP, using age, prostate-specific antigen (PSA), PSA density, body mass index, Sexual Health Inventory for Men score, American Urological Association symptom score, Charlson comorbidity index, prostate weight, preoperative Gleason score (GS), and history of smoking as variables. Surgical procedure S-RARP after FT was performed using a standardized technique developed at our institute with the da Vinci Xi Surgical System. Measurements Oncological and functional outcomes were compared between the S-RARP and primary RARP groups. Results and limitations There was no difference in estimated blood loss (p = 0.8) between the 1:1 matched groups, but operating room time was significantly longer for S-RARP (p = 0.007). The primary RARP group had a higher proportion of patients who underwent a full nerve-sparing procedure. The S-RARP group had higher incidence of positive surgical margins (40% vs 15%; p = 0.008), GS ≥8 (25% vs 15%; p = 0.07), and positive lymph node status (9.4% vs 5.7%; p = 0.02). There was no significant difference in overall complications between the groups. The primary RARP group had a higher incidence of lymphocele drainage after surgery (15% vs 0%; p = 0.006). The main limitation of the study is its retrospective design. Conclusions S-RALP after FT failure is feasible; however, surgery following FT leads to poorer oncological and functional outcomes. Despite the targeted nature of FT, significant nonfocal collateral damage is evident in tissues surrounding the prostate, which in turn translates to poorer functional outcomes after S-RARP. Patient summary We studied the surgical challenges during robot-assisted removal of the prostate after previous focal treatment (FT) for prostate cancer and compared the outcomes to those for robot-assisted prostate removal in patients who had no previous FT. We found that this technique is safe and effective with a limited risk of complications, but poor urinary and sexual functional outcomes.

Background: The Oncotype DX assay is a clinically validated 17-gene genomic assay that provides a genomic prostate score (GPS; scale 0-100) measuring the heterogeneous nature of prostate tumors. The test is performed on prostate tissue collected during biopsy. There is a lack of data on the association between the GPS and tumor pathology after radical prostatectomy (RP). Objective: To investigate the association between GPS and final pathology, including extra prostatic extension (EPE), positive surgical margin (PSM), and seminal vesicle invasion (SVI). Design, setting, and participants: Data for the 749 patients who underwent Oncotype DX assay and RP at a referral prostate cancer center between 2015 and 2019 were retrospectively assessed to evaluate the association between GPS and unfavorable pathology parameters. Intervention: After a GPS genetic test, patients underwent robotic RP performed by the same surgeon. Outcome measurement and statistical analysis: Multivariable logistic regression analyses were performed to assess the association between GPS and EPE, PSM, and SVI. The models were adjusted for age, clinical stage, prostate-specific antigen (PSA) level, Gleason score, and time between the genomic assay and surgery. The median time between Oncotype DX assay and surgery was 176 d (interquartile range [IQR] 141-226). The median age was 63 yr (IQR 58-68), median GPS was 29 (IQR 21-39), and median PSA was 5.7 ng/ml (IQR 4.6-7.7). In multivariable analyses assessing the odds ratio (OR) per 20-point change in GPS, GPS was an independent predictor of EPE (OR 1.8, 95% confidence interval [CI] 1.4-2.3) and SVI (OR 2.1, 95% CI 1.3-3.4). In addition, when patients were grouped by GPS quartile, the percentage of cases with EPE and SVI increased with the GPS quartile. Conclusions: We provide evidence that the Oncotype DX GPS is significantly associated with adverse pathology after RP. Specifically, the risk of EPE and SVI increases with the GPS. Therefore, use of the Oncotype DX GPS may help clinicians to improve preoperative patient counseling and develop surgical strategies for patients with a higher chance of EPE or unfavorable pathological features. Patient summary: We studied whether the score for a prostate genetic test was associated with prostate cancer pathology findings for patients who had their prostate removed. We found that the risk of prostate cancer spread outside the gland and to the seminal vesicle increases with higher test scores. These findings may help surgeons in counseling patients on surgical options for prostate cancer. (C) 2021 European Association of Urology. Published by Elsevier B.V. All rights reserved.

Introduction: To identify factors affecting potency and to predict ideal patient subgroups who will have the highest chance of being potent after robot-assisted laparoscopic prostatectomy (RALP) based on nerve sparing (NS). Materials and Methods: Analysis of 7268 patients who underwent RALP between 2008 and 2018 with a minimum of 12 months of follow-up was performed. The patients were then categorized into four separate neurovascular bundle-sparing groups (NVB 1-4). A Cox regression analysis was used to determine the independent factors predicting potency outcomes. Cumulative incidence functions were used to depict the probability and time to potency between the NS groups stratified by age and preoperative sexual health inventory in men (SHIM). Results: Cox regression analysis of age, preoperative SHIM score, and grades of NS significantly predicted potency outcomes post-RALP. Patients with SHIM score ≥22 had a better chance of potency vs patients with SHIM NVB 3. Conclusions: Preoperative SHIM, age, and NS are the most influential factors for potency recovery following RALP. Patients with good baseline sexual function had similar postoperative potency, irrespective of their grades of partial NS. In patients with decreased baseline SHIM and older age, a higher grade of partial NS resulted in a significantly better potency compared with a lower grade of partial nerve spare.

Some reports in the literature describe lymphocele formation in up to half of patients following pelvic lymph node dissection (PLND) in robotic-assisted radical prostatectomy (RARP), with 1-2% requ...

The da Vinci® single-port (SP) and multiport (Xi) approaches to robotic-assisted radical prostatectomy (RARP) are described by different authors in the literature, primarily comparing short-term outcomes of both modalities. To our knowledge, this is the first article comparing the surgical perspective and satisfaction of patients who underwent RARP with the SP and Xi platforms. To determine the patient surgical perspective and satisfaction in terms of pain control, return to normal activity, and overall results of surgery for two groups who underwent SP and Xi radical prostatectomy. The data from 71 consecutive patients who underwent SP RARP in a single center from June 2019 to April 2020 was compared to 875 patients who underwent Xi RARP in the same period. A single surgeon performed all procedures with a transperitoneal technique. After a propensity score match, two groups of 71 patients (SP and Xi) were selected and compared in the study. Patients were contacted by phone by two interviewers and a questionnaire was administered in English or Spanish. Patients were instructed not to disclose the type of robotic surgery they underwent, as interviewers were blinded to that information. A validated Surgical Satisfaction Questionnaire (SSQ-8) was used, along with an additional question from our institution asking about the satisfaction with the number of incision sites (GRI-1). Data were analyzed as continuous and discrete variables to compare the differences between the Xi and SP cohorts. A response rate of 85.9% (n = 61) in the Xi group and 73.2% (n = 52) in the SP group was captured. Overall satisfaction with surgical results was 80% and 88% in the Xi and SP cohorts, respectively. No statistical difference in responses was found between the Xi and SP cohorts for SSQ-8. However, GRI-1 demonstrated a statistically significant difference (P

Background Use of the single-port da Vinci SP robotic platform for various urological procedures has been described by several groups. However, the comparative performance of the SP robot in relation to earlier models such as the da Vinci Xi is still unclear. Objective To compare intraoperative and short-term postoperative outcomes between the da Vinci Xi and SP robots for patients undergoing radical prostatectomy (RP) in a referral center. Design, setting, and participants Data were prospectively collected for patients undergoing RP from June 2019 to April 2020 in a single center. The da Vinci SP was used for 71 patients and the da Vinci Xi for 875 patients. After propensity score (PS) matching, two groups of 71 patients were selected for the comparative study. Intervention RP via a transperitoneal approach using the same technique steps and anatomy access with both robot consoles. Outcome measurements and statistical analysis A PS analysis was performed using the covariates age, body mass index, Charlson comorbidity index, Sexual Health Inventory for Men score, American Urological Association symptom score, prostate size, prostate-specific antigen levels, Gleason score, D’Amico risk group, and degree of nerve-sparing. Intraoperative performance and short-term functional (continence and potency) and oncological outcomes were compared between the groups. Results and limitations Median follow-up was 4.4 mo (interquartile range [IQR] 1.6–7.2) for the SP group and 3.2 mo (IQR 1.6–4.8) for the Xi group (p = 0.2). The median total operative time and median console time were both significantly higher in the SP group, with median differences of 14 min (95% confidence interval [CI] 9–19) and 5 min (95% CI 0–5), respectively. The proportion of patients with blood loss of >100 ml was significantly lower in the SP group (difference of 27%, 95% CI 12–42%). No intra- or postoperative complications were reported in either group. There were no significant differences in pain scores at 6, 12, and 18 h or in positive surgical margin rates between the groups. The SP group had a significantly higher percentage of extraprostatic extension than the Xi group (difference of 16%, 95% CI 4.6–27%). None of the patients experienced biochemical recurrence during follow-up. The difference in continence rates at 45 d between the SP and Xi groups was 11% (95% CI −5.6% to 28%) and the difference in potency rates at 45 d was −7.3% (95% CI −21% to 6.2%). The short-term follow-up for comparison of functional and oncological outcomes is a limitation. Conclusions Despite differences in trocar placement and technology between the two da Vinci consoles, the SP has satisfactory intraoperative performance compared to the Xi. SP surgery can be performed safely and effectively during the initial learning phase. However, longer-term follow-up is needed to provide further evidence on the impact of SP implementation on functional and oncological outcomes. Patient summary We compared intraoperative and short-term postoperative outcomes for patients who underwent radical prostatectomy using two different robots, the da Vinci Xi and the single-port da Vinci SP. We found that operative time was longer for the Single Port console. Studies with long-term follow-up are needed to compare the functional and oncological outcomes.

Objective To assess the influence of the 2012 US Preventive Services Task Force (USPSTF) recommendation against prostate-specific antigen (PSA)-based screening on oncological and functional outcomes following robot-assisted laparoscopic prostatectomy (RALP). Materials and methods We retrospectively analysed patients who underwent RALP between 2008 and 2018 with a minimum of 12-month follow-up from a prospectively collected institutional review board-approved database. The impact of the USPSTF recommendation against PSA screening on our surgical outcomes was assessed using a logistic regression model using two groups comprising patients treated before/after the USPSTF statement and indicating time trends for each successive year. Results The mean preoperative PSA increased from 6.0 to 7.4 ng/mL after the USPSTF recommendation. We detected statistically significant time-trend changes after 2012, including an increase in the positive slope of Gleason ≥3 + 4 or ≥pT3 disease. We detected a fall in bilateral full nerve-sparing and an increase in partial nerve-sparing. The total positive surgical margin (PSM) rate increased after the USPSTF recommendation; however, PSM rates pertinent to each pathological stage did not change significantly after 2012. There was a significant negative trend change in the postoperative 12-month continence and potency rates, indicating a breakpoint in functional outcomes after 2012. We detected a 1.7-fold increase in 12-month biochemical recurrence (BCR) rates. The 12-month BCR, potency and continence rates were maintained in young ( 22 and low-volume disease. Conclusion Since the USPSTF's recommendation in 2012, we have seen a significant increase in the incidence of high-risk disease that has forced us to modify our approach to the procedure and the grade of nerve-sparing used, leading to a wider resection, in order to reduce PSMs. This has led to a decrease in postoperative functional recovery. Patients with favourable characteristics had good outcomes before and after the USPSTF's recommendation, implying that the quality of surgery did not change over time.

Background: The potassium channel encoded by the ether-a-gogo-related gene 1A (erg1a) has been detected in the atrophying skeletal muscle of mice experiencing either muscle disuse or cancer cachexia and further evidenced to contribute to muscle deterioration by enhancing ubiquitin proteolysis, however, to our knowledge, ERG1A has not been reported in human skeletal muscle. Methods and Results: Here, using immunohistochemistry, we detect ERG1A immunofluorescence in human Rectus abdominis skeletal muscle sarcolemma. Further, using single point brightness data, we report the detection of ERG1A immunofluorescence at low levels in the Rectus abdominis muscle sarcolemma of young adult humans and show that it trends toward greater levels (10.6%) in healthy aged adults. Interestingly, we detect ERG1A immunofluorescence at a statistically greater level (53.6%, p &lt, 0.05) in the skeletal muscle of older cancer patients than in age-matched healthy adults. Importantly, using immunoblot, we reveal that lower mass ERG1A protein is 61.5% (p &lt, 0.05) more abundant in the skeletal muscle of cachectic older adults than in healthy age-matched controls. Additionally, we report that the ERG1A protein is detected in a cultured human rhabdomyosarcoma line that may be a good in vitro model for the study of ERG1A in muscle. Conclusions: The data demonstrate that ERG1A is detected more abundantly in the atrophied skeletal muscle of cancer patients, suggesting it may be related to muscle loss in humans as it has been shown to be in mice experiencing muscle atrophy as a result of malignant tumors.

INTRODUCTION AND OBJECTIVE:In this study we propose a preoperative and post-operative nomogram to predict post-operative potency recovery following robot assisted laparoscopic prostatectomy (RALP)....

INTRODUCTION AND OBJECTIVE:Outcomes of 2 dedicated randomized controlled trials (RCTs) comparing on-clamp versus off-clamp robot-assisted (RPN) or pure laparoscopic partial nephrectomy (LPN) (CLOCK...

INTRODUCTION AND OBJECTIVE:Comprehensive systematic literature reviews including pure laparoscopic partial nephrectomy (LPN) showed no impact on either surgical or oncological outcomes by the off-c...

INTRODUCTION AND OBJECTIVE:There is a scarcity of information on the outcomes of robotic-assisted prostatectomy (RALP) in young men.To compare the age-stratified functional and oncological outcomes...

Background Evidence regarding clinically relevant effects of interventions aiming at reducing polypharmacy is weak, especially for the primary care setting. This study was initiated with the objective to achieve clinical benefits for older patients (aged 75+) by means of evidence-based reduction of polypharmacy (defined as ≥8 prescribed drugs) and inappropriate prescribing in general practice. Methods The cluster-randomised controlled trial involved general practitioners and patients in a northern-Italian region. The intervention consisted of a review of patient’s medication regimens by three experts who gave specific recommendations for drug discontinuation. Main outcome measures were non-elective hospital admissions or death within 24 months (composite primary endpoint). Secondary outcomes were drug numbers, hospital admissions, mortality, falls, fractures, quality of life, affective status, cognitive function. Results Twenty-two GPs/307 patients participated in the intervention group, 21 GPs/272 patients in the control group. One hundred twenty-five patients (40.7%) experienced the primary outcome in the intervention group, 87 patients (32.0%) in the control group. The adjusted rates of occurrence of the primary outcome did not differ significantly between the study groups (intention-to-treat analysis: adjusted odds ratio 1.46, 95%CI 0.99–2.18, p = 0.06; per-protocol analysis: adjusted OR 1.33, 95%CI 0.87–2.04, p = 0.2). Hospitalisations as single endpoint occurred more frequently in the intervention group according to the unadjusted analysis (OR 1.61, 95%CI 1.03–2.51, p = 0.04) but not in the adjusted analysis (OR 1.39, 95%CI 0.95–2.03, p = 0.09). Falls occurred less frequently in the intervention group (adjusted OR 0.55, 95%CI 0.31–0.98; p = 0.04). No significant differences were found regarding the other outcomes. Definitive discontinuation was obtained for 67 (16.0%) of 419 drugs rated as inappropriate. About 6% of the prescribed drugs were PIMs. Conclusions No conclusive effects were found regarding mortality and non-elective hospitalisations as composite respectively single endpoints. Falls were significantly reduced in the intervention group, although definitive discontinuation was achieved for only one out of six inappropriate drugs. These results indicate that (1) even a modest reduction of inappropriate medications may entail positive clinical effects, and that (2) focusing on evidence-based new drug prescriptions and prevention of polypharmacy may be more effective than deprescribing. Trial registration Current Controlled Trials (ID ISRCTN: 38449870), date: 11/09/2013.

Septic patients frequently develop skeletal muscle wasting and weakness, resulting in severe clinical consequences and adverse outcomes. Autophagy is a stress-induced degradative process essential to cell survival. Recent studies have demonstrated that sepsis triggers sustained induction of autophagy in skeletal muscles, although the impact of this enhanced autophagy on sepsis-induced muscle dysfunction remains unclear. Atg7 is an autophagy gene that plays a major role in autophagosome formation. Using an inducible and muscle-specific Atg7 knockout mouse model (Atg7iSkM-KO), we investigated the functional importance of skeletal muscle autophagy in sepsis. Sepsis was induced using cecal ligation and perforation (CLP) with a sham operation serving as a control. Atg7iSkM-KO mice exhibited a more severe phenotype in response to sepsis, marked by severe muscle wasting and contractile dysfunction, hypoglycemia, higher ketone levels and a decreased in survival as compared to mice with intact Atg7. Several genes that encode 26S proteasome subunits were upregulated, suggesting that activation of the ubiquitin-proteasome system is responsible for the severe muscle atrophy that was seen in these mice. Sepsis and Atg7 deletion resulted in the accumulation of mitochondrial dysfunction, although sepsis did not further worsen mitochondrial dysfunction in Atg7iSkM-KO mice. Overall, our study demonstrates that autophagy inactivation in skeletal muscles triggers significant worsening of sepsis-induced contractile and metabolic dysfunctions and negatively impacts survival. Induction of autophagy in skeletal muscles in response to sepsis thus represents a protective mechanism.

IL-6 is a pleiotropic cytokine that can exert different and opposite effects. The muscle-induced and transient expression of IL-6 can act in an autocrine or paracrine manner, stimulating anabolic pathways associated with muscle growth, myogenesis, and with regulation of energy metabolism. In contrast, under pathologic conditions, including muscular dystrophy, cancer associated cachexia, aging, chronic inflammatory diseases, and other pathologies, the plasma levels of IL-6 significantly increase, promoting muscle wasting. Nevertheless, the specific physio-pathological role exerted by IL-6 in the maintenance of differentiated phenotype remains to be addressed. The purpose of this study was to define the role of increased plasma levels of IL-6 on muscle homeostasis and the mechanisms contributing to muscle loss. Here, we reported that increased plasma levels of IL-6 promote alteration in muscle growth at early stage of postnatal life and induce muscle wasting by triggering a shift of the slow-twitch fibers toward a more sensitive fast fiber phenotype. These findings unveil a role for IL-6 as a potential biomarker of stunted growth and skeletal muscle wasting.

cited By 1 Skeletal muscle wasting is commonly associated with chronic kidney disease (CKD), resulting in increased morbidity and mortality. However, the link between kidney and muscle function remains poorly understood. Here, we took a complementary interorgan approach to investigate skeletal muscle wasting in CKD. We identified increased production and elevated blood levels of soluble pro-cachectic factors, including activin A, directly linking experimental and human CKD to skeletal muscle wasting programs. Single-cell sequencing data identified the expression of activin A in specific kidney cell populations of fibroblasts and cells of the juxtaglomerular apparatus. We propose that persistent and increased kidney production of procachectic factors, combined with a lack of kidney clearance, facilitates a vicious kidney/muscle signaling cycle, leading to exacerbated blood accumulation and, thereby, skeletal muscle wasting. Systemic pharmacological blockade of activin A using soluble activin receptor type IIB ligand trap as well as muscle-specific adeno-associated virus-mediated downregulation of its receptor ACVR2A/B prevented muscle wasting in different mouse models of experimental CKD, suggesting that activin A is a key factor in CKD-induced cachexia. In summary, we uncovered a crosstalk between kidney and muscle and propose modulation of activin signaling as a potential therapeutic strategy for skeletal muscle wasting in CKD.

Prediction of potency recovery following robot-assisted radical prostatectomy (RARP) is useful for better patient counseling and postoperative treatment strategies. In this study we propose a preoperative and postoperative nomogram to predict postoperative potency recovery following RARP.Patients from development set (6,502) were selected to develop the nomograms, and patients in validation set (2,706) were used for validation. Cox regression models were fitted on the development cohort to predict potency recovery after RARP using as prognostic factors the covariates selected. Two nomograms were drawn using the regression coefficients of the preoperative and postoperative Cox models.The discrimination ability of the preoperative model was evaluated on the development cohort using the receiver operator curves estimated at 3, 6, 12 and 24 months. The AUC at these time points was 0.726, 0.734, 0.754, and 0.778, respectively. The areas under the curve of the postoperative model at 3, 6, 12 and 24 months were 0.746, 0.756 and 0.777, and 0.801, respectively. Preoperative and postoperative predictive models were validated using a separate set of 2,706 patients. The AUCs of the preoperative model at 3, 6, 12 and 24 months were 0.789, 0.772, 0.768, and 0.778, respectively. The ROC curves of the postoperative model at 3, 6, 12 and 24 months with AUCs of 0.807, 0.797, 0.793 and 0.798, respectively. Along with age and preoperative sexual function, nerve-sparing technique determines the potency outcomes justifying better AUC for postoperative model vs the preoperative model.The above nomograms help us to predict with good accuracy the probability of potency recovery within 3, 6, 12 and 24 months following surgery taking into consideration preoperative and postoperative factors. This is a novel tool for the care giver to predict realistic expectation of potency outcomes to the patients, while preoperative and immediate postoperative counseling.

Objectives: To evaluate the role of the microbiological profile and of disease-related factors in the management of patients affected with Fournier’s gangrene (FG). Patients and methods: Data regarding patients admitted for FG at nine Italian Hospitals (March 2007–June 2018) were collected. Patients were stratified according to the number of microorganisms documented: Group A – one microorganism; Group B – two microorganisms; Group C – more than three microorganisms. Baseline blood tests, dedicated scoring systems, predisposing risk factors, disease’s features, management and post-operative course were analyzed. UpSet technique for visualizing set intersections in a matrix layout and Cuzick’s nonparametric test for trend across ordered groups were used. Results: Eighty-one patients were available for the analysis: 18 included in Group A, 32 in Group B, 31 in Group C. The most common microorganism isolated was Escherichia coli. In Group B-C, Escherichia coli was often associated to Enterococcus faecalis, Pseudomonas aeruginosa, and Klebsiella pneumoniae. Statistically significant positive association was highlighted among the number of pathogens (Group A vs B vs C) and serum C-reactive Protein ( p < 0.001), procalcitonin ( p = 0.02) and creatinine ( p = 0.03). Scoring systems were associated with the number of microorganisms detected ( p < 0.02). A significant association between the number of microorganisms and the use of VAC therapy and need of a fecal diversion was found ( p < 0.02). The number of microorganisms was positively associated with the length of stay (LOS) ( p = 0.02). Ten weeks after initial debridement, wound closure was achieved in 11 (91.7%), 22 (84.6%) and 20 (80%) patients in Group A, B, and C, respectively, with no differences in overall survival. Conclusion: Polymicrobial infections in FG are positively associated with inflammatory scores, the need for fecal diversion and the LOS. This results may help the counseling and the clinical management of this rare niche of patients.

Background The impact of the type and the severity of disability on whole-body and regional body composition (BC), and bone mineral density (BMD) must be considered for dietary advice in athletes with a physical impairment (PI). This study aimed to investigate the impact of the type and the severity of disability on BC, the pattern of distribution of fat mass at the regional level, and BMD in athletes with a PI. Methods Forty-two male athletes with spinal cord injury (SCI, n = 24; age = 40.04 ± 9.95 years, Body Mass Index [BMI] = 23.07 ± 4.01 kg/m2) or unilateral lower limb amputation (AMP, n = 18; age = 34.39 ± 9.19 years, BMI = 22.81 ± 2.63 kg/m2) underwent a Dual-Energy X-Ray Absorptiometry scan. Each athlete with a PI was matched by age with an able-bodied athlete (AB, n = 42; age = 37.81 ± 10.31 years, BMI = 23.94 ± 1.8 kg/m2). Results One-Way Analysis of Variance showed significant differences between the SCI, AMP and AB groups for percentage fat mass (%FM) (P < 0.001, eta squared = 0.440). Post-hoc analysis with Bonferroni’s correction showed that athletes with SCI had significantly higher %FM vs. the AMP and AB groups (25.45 ± 5.99%, 21.45 ± 4.21% and 16.69 ± 2.56%, respectively; P = 0.008 vs. AMP and P < 0.001 vs. AB). The %FM was also significantly higher in the AMP vs. the AB group (P < 0.001). Whole-body BMD was negatively affected in SCI athletes, with about half of them showing osteopenia or osteoporosis. In fact, the mean BMD and T-score values in the SCI group (1.07 ± 0.09 g/cm2 and −1.25 ± 0.85, respectively) were significantly lower in comparison with the AB group (P = 0.001 for both) as well as the AMP group (P = 0.008 for both). The type of disability affected BC and BMD in the trunk, android, gynoid and leg regions in SCI athletes and the impaired leg only in AMP athletes. Conclusions In conclusion, the type of disability and, partly, the severity of PI impact on BC and BMD in athletes with a PI. Nutritionists, sports medicine doctors, clinicians, coaches and physical conditioners should consider athletes with SCI or AMP separately. Athletes with a PI would benefit from specific nutrition and training programs taking into account the type of their disability.

OBJECTIVES To evaluate the clinical trend changes in our robot-assisted laparoscopic prostatectomy (RALP) practice and to investigate the effect of 2012 US Preventive Services Task Force (USPSTF) statement against PSA screening on these trends. PATIENTS AND METHODS Data of 10 000 RALPs performed by a single surgeon between 2002 and 2017 were retrospectively analysed. Time trends in successive 1000 cases for clinical, surgical and pathological characteristics were analysed with linear and logistic regression. Time-trend changes before and after the USPSTF's statement were compared using a logistic regression model and likelihood-ratio test. RESULTS Unfavourable cancer characteristics rate, including D'Amico high risk, pathological non-organ-confined disease and Gleason score ≥4+4 increased from 11.5% to 23.3%, 14% to 42.5%, and 7.7% to 20.9%, respectively, over time (all P

Purpose:We sought to identify predictive factors of the transition from off clamp to on clamp robotic partial nephrectomy following an intraoperative decision.Materials and Methods:In the multicent...

CNPq - Conselho Nacional de Desenvolvimento Científico e Tecnológico CAPES - Coordenação de Aperfeiçoamento de Pessoal de Nível Superior FAPESP - Fundação de Amparo à Pesquisa do Estado de São Paulo Outra Agência Background: Stimulation of β2 -adrenoceptors can promote muscle hypertrophy and fibre type shift, and it can counteract atrophy and weakness. The underlying mechanisms remain elusive. Methods: Fed wild type (WT), 2-day fasted WT, muscle-specific insulin (INS) receptor (IR) knockout (M-IR-/- ), and MKR mice were studied with regard to acute effects of the β2 -agonist formoterol (FOR) on protein metabolism and signalling events. MKR mice express a dominant negative IGF1 receptor, which blocks both INS/IGF1 signalling. All received one injection of FOR (300 μg kg-1 subcutaneously) or saline. Skeletal muscles and serum samples were analysed from 30 to 240 min. For the study of chronic effects of FOR on muscle plasticity and function as well as intracellular signalling pathways, fed WT and MKR mice were treated with formoterol (300 μg kg-1 day-1 ) for 30 days. Results: In fed and fasted mice, one injection of FOR inhibited autophagosome formation (LC3-II content, 65%, P ≤ 0.05) that was paralleled by an increase in serum INS levels (4-fold to 25-fold, P ≤ 0.05) and the phosphorylation of Akt (4.4-fold to 6.5-fold, P ≤ 0.05) and ERK1/2 (50% to two-fold, P ≤ 0.05). This led to the suppression (40-70%, P ≤ 0.05) of the master regulators of atrophy, FoxOs, and the mRNA levels of their target genes. FOR enhanced (41%, P ≤ 0.05) protein synthesis only in fed condition and stimulated (4.4-fold to 35-fold, P ≤ 0.05) the prosynthetic Akt/mTOR/p70S6K pathway in both fed and fasted states. FOR effects on Akt signalling during fasting were blunted in both M-IR-/- and MKR mice. Inhibition of proteolysis markers by FOR was prevented only in MKR mice. Blockade of PI3K/Akt axis and mTORC1, but not ERK1/2, in fasted mice also suppressed the acute FOR effects on proteolysis and autophagy. Chronic stimulation of β2 -adrenoceptors in fed WT mice increased body (11%, P ≤ 0.05) and muscle (15%, P ≤ 0.05) growth and downregulated atrophy-related genes (30-40%, P ≤ 0.05), but these effects were abolished in MKR mice. Increases in muscle force caused by FOR (WT, 24%, P ≤ 0.05) were only partially impaired in MKR mice (12%, P ≤ 0.05), and FOR-induced slow-to-fast fibre type shift was not blocked at all in these animals. In MKR mice, FOR also restored the lower levels of muscle SDH activity to basal WT values and caused a marked reduction (57%, P ≤ 0.05) in the number of centrally nucleated fibers. Conclusions: NS/IGF1 signalling is necessary for the anti-proteolytic and hypertrophic effects of in vivo β2 -adrenergic stimulation and appears to mediate FOR-induced enhancement of protein synthesis. INS/IGF1 signalling only partially contributes to gain in strength and does not mediate fibre type transition induced by FOR

Background A precondition for developing strategies to reduce polypharmacy and its well-known harmful consequences is to study its epidemiology and associated factors. The objective of this study was to analyse the prevalence of polypharmacy (defined as ≥8 prescribed drugs), of potentially inappropriate medications (PIMs) and major drug-drug interactions (DDIs) among community-dwelling general practice patients aged ≥75 years and to identify characteristics being associated with polypharmacy. Methods This cross-sectional study is derived from baseline data (patients’ demographic/biometric characteristics, diagnoses, medication-related data, cognitive/affective status, quality of life) of a northern-Italian cluster-RCT. PIMs and DDIs were assessed using the 2012 Beers criteria and the Lexi-Interact® database. Data were analysed using descriptive methods, Wilcoxon rank-sum tests, Fisher’s exact tests and Spearman correlations. Results Of the eligible patients aged 75+, 13.4% were on therapy with ≥8 drugs. Forty-three general practitioners and 579 patients participated in the study. Forty five point nine percent of patients were treated with ≥1 Beers-listed drugs. The most frequent PIMs were benzodiazepines/hypnotics (19.7% of patients) and NSAIDs (6.6%). Sixty seven point five percent of patients were exposed to ≥1 major DDI, 35.2% to ≥2 major DDIs. Antithrombotic/anticoagulant medications (30.4%) and antidepressants/antipsychotics (23.1%) were the most frequently interacting drugs. Polypharmacy was significantly associated with a higher number of major DDIs (Spearman’s rho 0.33, p p p = 0.003) and lower EQ-5D-5L scores (thus, lower quality of life) (Spearman’s rho − 0.14, p = 0.001). Patients’ age/sex, 6-CIT scores (cognitive status), BMI or PIM use were not correlated with the number of drugs. Conclusions The prevalence of polypharmacy, PIMs and major DDIs was considerable. Results indicate that physicians should particularly observe their patients with multiple conditions, reduced health and affective status, independently from other patients’ characteristics. Careful attention about indication, benefit and potential risk should be paid especially to patients on therapy with specific drug classes identified as potentially inappropriate or prone to major DDIs in older persons (e.g., benzodiazepines, NSAIDs, protonic pump inhibitors, antithrombotics/anticoagulants, antidepressants/antipsychotics). Trial registration The cluster-RCT on which this cross-sectional analysis is based was registered with Current Controlled Trials Ltd. (ID ISRCTN: 38449870) on 2013-09-11.

KEY POINTS Few days of unloading are sufficient to induce a decline of skeletal muscle mass and function; notably, contractile force is lost at a faster rate than muscle mass. The reasons behind this disproportionate loss of muscle force are still poorly understood. We provide strong evidence of two mechanisms only hypothesized until now for the rapid muscle force loss in only 10 days of bed rest. Our results show that an initial neuromuscular junction instability, accompanied by alterations in the innervation status and impairment of single fibre sarcoplasmic reticulum function contribute to the loss of contractile force in front of a preserved myofibrillar function and central activation capacity. Early onset of neuromuscular junction instability and impairment in calcium dynamics involved in excitation-contraction coupling are proposed as eligible determinants to the greater decline in muscle force than in muscle size during unloading. ABSTRACT Unloading induces rapid skeletal muscle atrophy and functional decline. Importantly, force is lost at a much higher rate than muscle mass. We aimed to investigate the early determinants of the disproportionate loss of force compared to that of muscle mass in response to unloading. Ten young participants underwent 10 days of bed rest (BR). At baseline (BR0) and at 10 days (BR10), quadriceps femoris (QF) volume (VOL) and isometric maximum voluntary contraction (MVC) were assessed. At BR0 and BR10 blood samples and biopsies of vastus lateralis (VL) muscle were collected. Neuromuscular junction (NMJ) stability and myofibre innervation status were assessed, together with single fibre mechanical properties and sarcoplasmic reticulum (SR) calcium handling. From BR0 to BR10, QFVOL and MVC decreased by 5.2% (P = 0.003) and 14.3% (P

We assess factors/additional morbidities related to the conversion of clamping approach during off-clamp vs on-clamp laparoscopic partial nephrectomy in the setting of a randomized study.Consecutive candidates for laparoscopic partial nephrectomy from 6 institutions were randomized to on-clamp or off-clamp surgery. The present study analyzed 1) off-clamp arm patients, comparing the procedures finalized per protocol without artery clamping (off-clamp) to those needing renal artery clamping (shift-on-clamp) and 2) on-clamp arm patients, comparing the procedures finalized with artery clamping (on-clamp) to those completed without clamping (shift-off-clamp).A total of 123 patients were randomized to on-clamp and 126 to off-clamp surgery. Of the off-clamp patients 41 (32.5%) converted to on-clamp. Of the on-clamp patients 70 (56.9%) completed surgery without clamping the renal artery due to subjective intraoperative decision of the surgeon. Tumor size was greater in shift-on-clamp vs off-clamp cases (4 vs 3, p=0.002). Conversely, tumor size (3.7 vs 3 cm, p=0.002) and R.E.N.A.L. nephrometry score (6 vs 5, p=0.038) were lower in shift-off-clamp cases. Shift-on-clamp cases had longer operative times and greater changes in estimated glomerular filtration rate on postoperative day 1. Shift-off-clamp cases had shorter operative times. A higher proportion of patients who completed on-clamp surgery per protocol had a greater than 25% drop in estimated glomerular filtration rate on postoperative day 1 (29.4%) compared to smaller changes (10.3%, p=0.009) in estimated glomerular filtration rate. Increasing tumor size and complete endophytic growth pattern predicted shift-on-clamp while preventing shift-off-clamp. Body mass index above 28 predicted shift-off-clamp.The likelihood of shift-on/off-clamp relies on tumor size/complexity. The intraoperative need to convert the planned strategy seemed harmless on postoperative course. An advantage in terms of early functional outcomes does exist when avoiding artery clamping.

Objective Italy is facing the COVID‐19 outbreak with an abrupt reorganization of its national health‐system, in order to augment care provision to symptomatic patients. The sudden shift of personnel and resources towards COVID‐19 care has led to the reduction of surgery, with possible severe drawbacks. The aim of the study is to describe the trend in surgical volume in urology, in Italy. Materials and Methods Thirty‐three urological units with physicians affiliated to the AGILE consortium were involved in a survey. Urologists were asked to report the amount of surgical elective procedures week‐by‐week, from the beginning of the emergency to the following month. Results The 33 hospitals involved in the study account, globally, for 22,945 beds and are distributed in 13/20 Italian regions. Before the outbreak, the involved urology units performed an overall amount of 1,213 procedures per week, half of which were oncological. One month later, the amount of surgery declined by 78%. Lombardy, the first region with positive‐cases, experienced a 94% reduction. The decrease in oncological and non‐oncological surgical activity was 35,9% and 89%, respectively. The trend of the decline showed a delay of roughly 2 weeks for the other regions. Conclusion Italy, the country with the highest fatality rate from COVID‐19, is experiencing a sudden decline in surgical activity. It is inversely related to the increase in COVID‐19 care, with potential harm particularly in the oncological field. The Italian experience can be helpful for future surgical pre‐planning in other countries not so hardly hit by the disease yet.

To retrospectively review our 20 year experience of multidisciplinary management of non-metastatic ductal prostate cancer (dPC), a rare but aggressive histological subtype of prostate cancer whose optimal therapeutic approach is still controversial. Histologically confirmed dPC patients undergoing primary, curative treatment [radical prostatectomy (RP), external beam radiotherapy (EBRT), and androgen deprivation therapy (ADT)] were included, and percentage of ductal and acinar pattern within prostate samples were derived. Survival outcomes were assessed using the subdistribution hazard ratio (SHR) and Fine-and-Gray model. From January 1997 to December 2016, 81 non-metastatic dPC fitted selection criteria. Compared to surgery alone, SHR for progression-free survival and cancer-specific mortality were 2.8 (95% CI 0.6–13.3) and 1.3 (95% CI 0.1–16.2) for exclusive EBRT, 2.7 (95% CI 0.6–13.0) and 6.5 (95% CI 0.6–69.8) for adjuvant EBRT, 4.9 (95% CI 0.7–35.5) and 5.8 (95% CI 0.5–65.6) for salvage EBRT post-prostatectomy recurrence, and 3.2 (95% CI 0.7–14.0) and 3.9 (95% CI 0.3–44.1) for primary ADT (P = 0.558; P = 0.181), respectively. Comparing multimodal treatment and monotherapy confirmed the above trends. Local recurrence more typically occurred in pure dPC patients, mixed histology more frequently produced metastatic spread (29.6% relapse in total, P = 0.026). Albeit some limitations affected the study, our findings support the role of local treatment to achieve better disease control and improve quality of life. Different behavior, with typical local growth in pure dPC, higher distant metastatization in the mixed form, might influence treatment response. Given its poor prognosis, we recommend multidisciplinary management of dPC.

Purpose To explore the role of vacuum assisted closure (VAC) therapy versus conventional dressings in the Fournier’s gangrene wound therapy. Patients and Methods This is a retrospective multi-institutional cohort study. Data of 92 patients from nine centers between 2007 and 2018 were retrospectively analyzed. After surgery, patient having a local or a disseminated FG were managed with VAC therapy or with conventional dressings. The 10-weeks wound closure cumulative rate and OS were analyzed. Results Of the 92 patients, 62 (67.4%) showed local and 30 (32.6%) a disseminated FG. After surgery, 19 patients (20.7%) with local and 14 (15.2%) with disseminated FG underwent to VAC therapy; 43 (46.7%) with local and 16 (17.4%) with disseminated FG were treated using conventional dressings. The multivariable logistic regression analysis demonstrated that the VAC in patients with disseminated FG led to a higher cumulative rate of wound closure than patients treated with no-VAC (OR = 6.5; 95% CI 1.1–37.4, p = 0.036). The Kaplan–Meier survival curves for the OS showed a significant difference between no-VAC patients with local and disseminated FG (OS rate at 90 days 0.90, 95% CI 0.71–0.97 vs 0.55, 95% CI 0.24–0.78, respectively; p = 0.039). Cox regression confirmed that no-VAC patients with disseminated FG showed the lowest OS (hazard ratio adjusted for sex and age HR = 3.4, 95% CI 1.1–10.4; p = 0.033). Conclusions In this large cohort study, VAC therapy in patients with disseminated FG may offer an advantage in terms of 10-weeks wound closure cumulative rate and OS at 90 days after initial surgery.

Purpose The Ubiquitin Proteasome System (UPS) is a selective degradation system mediating the removal of intracellular unfolded/misfolded proteins and is essential for cardiomyocyte (CM) health. Substrate specificity and ubiquitination rate are mediated by E3 ubiquitin-ligases, such as Atrogin1 and MuRF1, which are specifically expressed in muscle cells. Perturbation of protein quality control causes aggregation of misfolded proteins, leading to CM proteotoxicity. UPS dysfunction occurs in ageing, a risk factor for cardiac hypertrophy and HF. We recently demonstrated that Atrogin-1 is essential to maintain CM health, during ageing. Whether MuRF1 plays similar roles in heart adaptation to ageing is still unexplored, and different studies have yielded contrasting results. Methods To assess the role of MuRF1 in heart homeostasis, we combined echocardiography, histology, IF, TUNEL assay and EM on heart sections from MuRF1 knock-out (KO) mice, and littermate controls, at 3, 10 and 24 mo. RTqPCR and WB assessed markers of UPS and extracellular matrix. Langendorff procedure was used to separate CMs from cardiac fibroblasts. Molecular and IF analyses were performed in heart samples from patients affected by aortic stenosis. Results MuRF1 ablation leads to cardiac hypertrophy, progressing during ageing (LV CM areas: 3 mo., KO: 329.14±10.66 vs Ctrl: 296.25±5.43; 10 mo., KO: 399.73±7.64 vs Ctrl: 247.49±3.67; 24 mo., KO: 418.89±11.10 vs. Ctrl: 209.93±4.48, in μm2). The hypertrophic remodeling was accompanied by diastolic dysfunction in the adulthood and, during ageing, also by systolic dysfunction (EF, 24 mo., KO: 29.55±8.82 vs Ctrl: 51.23±6.56, in %). Loss of MuRF1 causes increased interstitial collagen -I and -VI deposition, even before the onset of contractile dysfunction, followed by activation of Matrix MetalloProteinases (MMPs), suggesting that such alterations may be responsible for decreased cardiac performance. Interestingly, collagen established rings enveloping MuRF1 KO CMs and such fibrotic remodeling was not accompanied by increased CM apoptosis, nor myofibroblast activation. Such peculiar remodelling, called peri-endomysial fibrosis, was detected in hearts from patients with aortic stenosis, a condition in which MuRF1 levels decrease. Our data supports that MuRF1 has a role in CM-dependent regulation of the extracellular matrix (ECM) dynamics. Consistently, MuRF1 downregulation in normal cultured CMs demonstrated that such ubiquitin ligase impacts on signaling pathways involved in the control of the ECM homeostasis. In addition, fibroblasts treated with culture medium conditioned by MuRF1 KO CM display increased collagen and MMP expression. Conclusions We identifieded a novel role of MuRF1 in the control of CM proteostasis, and unveiled that in addition to cardiac fibroblasts, CM may directly regulate ECM dynamics, indicating that the correct function of MuRF1 is essential for heart adaptation to aging. Funding Acknowledgement Type of funding source: Public grant(s) – National budget only. Main funding source(s): University of Padova

Introduction: COVID-19 outbreak represented an unprecedented event that led to a redefinition of health care systems worldwide The impact of the emergency required a deviation of the care toward the assistance to COVID-19 patients, with reduction of resources for elective activities, including surgery We aim to report the decrease of urological surgical activity during the first weeks from the beginning of the pandemic, aiming to highlight the prioritization we applied to select patients for surgery Materials and methods: Thirty-three urological units with physicians affiliated to the AGILE group were involved in a survey Urologists were asked to report the amount of surgical elective procedures week- by-week, from the beginning of the emergency to the following month The type of surgery (oncologic, for urolithiasis, for benign prostate obstruction, other) was assessed as well Results: The 33 hospitals involved in the study account, globally, for 22,945 beds and are distributed in 13/20 Italian regions Before the outbreak, the involved urology units performed an overall amount of 1,213 procedures per week, half of which were oncological By the 20 of March, the amount of surgery declined by 78% Lombardy, the first region with positive-cases, experienced a 94% reduction The decrease in oncological and non- oncological surgical activity was 35,9% and 89%, respectively Among non-oncological procedures, stone surgery declined by 35,9% as well, whereas BPH and minor urological procedures completely dropped Reassessing for surgical activity on 20, April, a slight trend toward surgical restoration (+11%) started to appear Conclusions: Italy, the country with the highest fatality rate from COVID-19, had experienced a sudden decline in surgical activity;by the end of April, a current trend toward restoration of surgery started to appear Criteria for prioritization were consistent with an urgent/ emergent principle, with trauma, tumours and septic conditions being the ones prioritized The Italian experience can be helpful for future surgical pre-planning in other countries or pandemic settings Smart Communications (SC1–SC28) Andrology

Background: VOCs originate from metabolic pathophysiological processes at respiratory and systemic level. VOCs pattern has previously been analysed with E-nose on exhaled air; in CF it distinguished P.aeruginosa and A.fumigatus colonization. Aim: to evaluate exhaled VOCs pattern with E-nose (Cyranose320®)in HC and in CF pts; to compare exhaled VOCs in stable CF pts (StCF) and in pts with respiratory exacerbation (ExCF). Methods: a cross-sectional experimental study was approved by Verona Ethic Committee. Spirometry, N2multiple breath washout (MBW) and exhaled air collection were performed in 29 CF pts (age 12.56 ± 4.08; 23 StCF, 6 ExCF) and 15 HC (age 13.36 ±4.13). VOCs analysis was performed with Cyranose320®. The output data underwent multivariate analysis and Principal Component Analysis (PCA). Results: A number of E-nose sensors (S6-8, S10, S12, S21, S27, S28) significantly distinguished between HC and CF pts; also, StCF could be discriminated from ExCf (S6-8, S10, S12, S21, S27). For sensors distinguishing between HC and CF pts, AUC of ROC was more than accurate for S12 (0.85), good for S6-7, S21, S27 (0.73-0.76). PCA identified PC10, PC1, PC7 and PC2, which proved the best PC in predicting between HC and CF subsets. Spirometry distinguished HC from ExCF, but not from St CF, whereas N2MBW distinguished also StCF from HC. Conclusion: E-nose analysis of exhaled air samples distinguished HC from CF pts, and among CF pts, StCF from ExCF. N2MBW distinguished all 3 subsets, whereas spirometry only distinguished ExCF from HC. E-nose is a promising tool for clinical and research setting.

Aging is associated with alterations in skeletal muscle autophagy, potentially affecting both muscle mass and quality in a negative manner. Strength training with protein supplementation has been reported to improve both muscle mass and quality in frail elderly individuals, but whether improvements are accompanied by alterations in protein quality control is not known. To address this issue, we investigated protein degradation markers in skeletal muscle biopsies (m. vastus lateralis) from twenty-four frail elderly men and women (86 ± 7 yr) after acute and chronic (10 weeks) strength training with protein supplementation (ST + PRO) or protein supplementation alone (PRO). Acute increases in mRNA expression of genes related to the ubiquitin proteasome system (MuRF-1, MUSA1), autophagy (ATG7, LC3, p62), and mitochondrial fission (DRP1) were observed after the first, but not after the last training session in ST + PRO. Acute changes in gene expression were accompanied by changes in protein levels of both LC3-I and LC3-II. Hence, the acute training-induced activation of proteasomal degradation and autophagy seems to depend on training status, with activation in the untrained, but not trained state. The ten-week training intervention did not affect basal levels of autophagy mRNAs and proteins, and neither markers of the ubiquitin-proteasome system. This suggests that a relatively short period of strength training may not be sufficient to increase the basal rate of protein degradation in frail elderly.

Objectives To report the frequency and characteristics of growth hormone (GH) deficiency (GHD) in adolescents who had normalized GH secretion at mid-puberty and to identify possible factors predictive for GH sufficiency at puberty. Design Clinical analysis of children affected by GHD at five time points: diagnosis; first year of therapy; intermediate stage of puberty; retesting and end of growth phase. Methods The study population was 80 children with idiopathic GHD and treated with GH for at least 2 years. Treatment was discontinued at the intermediate stage of puberty. Retesting with an arginine test was performed 12 weeks later. If GH peak at retesting was ≥8 μg/L, the therapy was definitively discontinued, otherwise it was restarted and continued until achievement of near-final height. Results GH therapy was discontinued in 44 children (55%), and restarted in 36 (45%). No evidence of differences in definitive height and in the delta height between the genetic target and the definitive height was found between the two groups. The only predictive factor for GHD at mid-puberty was the insulin growth factor-1 (IGF-1) level at 1 year of GH treatment. Conclusions GH secretion should be retested at mid-puberty. Retesting at puberty may reduce potential side effects and minimize costs, without impairing growth potential and final height.

Polyglutamine (polyQ) expansions in the androgen receptor (AR) gene cause spinal and bulbar muscular atrophy (SBMA), a neuromuscular disease characterized by lower motor neuron (MN) loss and skeletal muscle atrophy, with an unknown mechanism. We generated new mouse models of SBMA for constitutive and inducible expression of mutant AR and performed biochemical, histological and functional analyses of phenotype. We show that polyQ-expanded AR causes motor dysfunction, premature death, IIb-to-IIa/IIx fiber-type change, glycolytic-to-oxidative fiber-type switching, upregulation of atrogenes and autophagy genes and mitochondrial dysfunction in skeletal muscle, together with signs of muscle denervation at late stage of disease. PolyQ expansions in the AR resulted in nuclear enrichment. Within the nucleus, mutant AR formed 2% sodium dodecyl sulfate (SDS)-resistant aggregates and inclusion bodies in myofibers, but not spinal cord and brainstem, in a process exacerbated by age and sex. Finally, we found that two-week induction of expression of polyQ-expanded AR in adult mice was sufficient to cause premature death, body weight loss and muscle atrophy, but not aggregation, metabolic alterations, motor coordination and fiber-type switch, indicating that expression of the disease protein in the adulthood is sufficient to recapitulate several, but not all SBMA manifestations in mice. These results imply that chronic expression of polyQ-expanded AR, i.e. during development and prepuberty, is key to induce the full SBMA muscle pathology observed in patients. Our data support a model whereby chronic expression of polyQ-expanded AR triggers muscle atrophy through toxic (neomorphic) gain of function mechanisms distinct from normal (hypermorphic) gain of function mechanisms.

Background A microscopic analysis of tissue is the gold standard for cancer detection. Hematoxylin-eosin (HE) for the reporting of prostate biopsy (PB) is conventionally based on fixation, processing, acquisition of glass slides, and analysis with an analog microscope by a local pathologist. Digitalization and real-time remote access to images could enhance the reporting process, and form the basis of artificial intelligence and machine learning. Fluorescence confocal microscopy (FCM), a novel optical technology, enables immediate digital image acquisition in an almost HE-like resolution without requiring conventional processing. Objective The aim of this study is to assess the diagnostic ability of FCM for prostate cancer (PCa) identification and grading from PB. Design, setting, and participants This is a prospective, comparative study evaluating FCM and HE for prostate tissue interpretation. PBs were performed (March to June 2019) at a single coordinating unit on consecutive patients with clinical and laboratory indications for assessment. FCM digital images (n = 427) were acquired immediately from PBs (from 54 patients) and stored; corresponding glass slides (n = 427) undergoing the conventional HE processing were digitalized and stored as well. A panel of four international pathologists with diverse background participated in the study and was asked to evaluate all images. The pathologists had no FCM expertise and were blinded to clinical data, HE interpretation, and each other’s evaluation. All images, FCM and corresponding HE, were assessed for the presence or absence of cancer tissue and cancer grading, when appropriate. Reporting was gathered via a dedicated web platform. Outcome measurements and statistical analysis The primary endpoint is to evaluate the ability of FCM to identify cancer tissue in PB cores (per-slice analysis). FCM outcomes are interpreted by agreement level with HE (K value). Additionally, either FCM or HE outcomes are assessed with interobserver agreement for cancer detection (presence vs absence of cancer) and for the discrimination between International Society of Urologic Pathologists (ISUP) grade = 1 and ISUP grade > 1 (secondary endpoint). Results and limitations Overall, 854 images were evaluated from each pathologist. PCa detection of FCM was almost perfectly aligned with HE final reports (95.1% of correct diagnosis with FCM, κ = 0.84). Inter-rater agreement between pathologists was almost perfect for both HE and FCM for PCa detection (0.98 for HE, κ = 0.95; 0.95 for FCM, κ = 0.86); for cancer grade attribution, only a moderate agreement was reached for both HE and FCM (HE, κ = 0.47; FCM, κ = 0.49). Conclusions FCM provides a microscopic, immediate, and seemingly reliable diagnosis for PCa. The real-time acquisition of digital images—without requiring conventional processing—offers opportunities for immediate sharing and reporting. FCM is a promising tool for improvements in cancer diagnostic pathways. Patient summary Fluorescence confocal microscopy may provide an immediate, microscopic, and apparently reliable diagnosis of prostate cancer on prostate biopsy, overcoming the standard turnaround time of conventional processing and interpretation.